Takuya Seike

All Publications

• Impact of common ALDH2 inactivating mutation and alcohol consumption on Alzheimer's disease. Frontiers in aging neuroscience Seike, T., Chen, C. H., Mochly-Rosen, D. 2023; 15: 1223977

  Abstract

  Aldehyde dehydrogenase 2 (ALDH2) is an enzyme found in the mitochondrial matrix that plays a central role in alcohol and aldehyde metabolism. A common ALDH2 polymorphism in East Asians descent (called ALDH2*2 or E504K missense variant, SNP ID: rs671), present in approximately 8% of the world's population, has been associated with a variety of diseases. Recent meta-analyses support the relationship between this ALDH2 polymorphism and Alzheimer's disease (AD). And AD-like pathology observed in ALDH2-/- null mice and ALDH2*2 overexpressing transgenic mice indicate that ALDH2 deficiency plays an important role in the pathogenesis of AD. Recently, the worldwide increase in alcohol consumption has drawn attention to the relationship between heavy alcohol consumption and AD. Of potential clinical significance, chronic administration of alcohol in ALDH2*2/*2 knock-in mice exacerbates the pathogenesis of AD-like symptoms. Therefore, ALDH2 polymorphism and alcohol consumption likely play an important role in the onset and progression of AD. Here, we review the data on the relationship between ALDH2 polymorphism, alcohol, and AD, and summarize what is currently known about the role of the common ALDH2 inactivating mutation, ALDH2*2, and alcohol in the onset and progression of AD.

  View details for DOI 10.3389/fnagi.2023.1223977

  View details for PubMedID 37693648

  View details for PubMedCentralID PMC10483235

• Hydroxynonenal Causes Hepatocyte Death by Disrupting Lysosomal Integrity in Nonalcoholic Steatohepatitis CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY Seike, T., Boontem, P., Yanagi, M., Li, S., Kido, H., Yamamiya, D., Nakagawa, H., Okada, H., Yamashita, T., Harada, K., Kikuchi, M., Shiraishi, Y., Ozaki, N., Kaneko, S., Yamashima, T., Mizukoshi, E. 2022; 14 (4): 925-944

  Abstract

  The lipid oxidation is a key factor for damaging hepatocytes and causing cell death. However, the mechanisms underlying hepatocyte death and the role of the most popular lipid peroxidation product 4-hydroxy-2-nonenal (HNE) in nonalcoholic steatohepatitis (NASH) remains unclear.We demonstrated using hepatoma cell lines, a NASH mouse model, HNE-treated monkeys, and biopsy specimens from patients with NASH that HNE induced hepatocyte death by disintegrating the lysosomal limiting membrane.The degree of HNE deposition in human NASH hepatocytes was more severe in cases with high lobular inflammation, ballooning, and fibrosis scores, and was associated with enlargement of the staining of lysosomes in hepatocytes. In in vitro experiments, HNE activated μ-calpain via G-protein coupled receptor (GPR) 120. The resultant rupture/permeabilization of the lysosomal limiting membrane induced the leakage of cathepsins from lysosomes and hepatocyte death. The blockade of G-protein coupled receptor 120 (GPR120) or μ-calpain expression suppressed lysosomal membrane damage and hepatocyte death by HNE. Alda-1, which activates aldehyde dehydrogenase 2 to degrade HNE, prevented HNE-induced hepatocyte death. Intravenous administration of HNE to monkeys for 6 months resulted in hepatocyte death by a mechanism similar to that of cultured cells. In addition, intraperitoneal administration of Alda-1 to choline-deficient, amino-acid defined treated mice for 8 weeks inhibited HNE deposition, decreased liver inflammation, and disrupted lysosomal membranes in hepatocytes, resulting in improvement of liver fibrosis.These results provide novel insights into the mechanism of hepatocyte death in NASH and will contribute to the development of new therapeutic strategies for NASH.

  View details for DOI 10.1016/j.jcmgh.2022.06.008

  View details for Web of Science ID 000861730300004

  View details for PubMedID 35787976

  View details for PubMedCentralID PMC9500440

• Fatty acid-driven modifications in T-cell profiles in non-alcoholic fatty liver disease patients JOURNAL OF GASTROENTEROLOGY Seike, T., Mizukoshi, E., Yamada, K., Okada, H., Kitahara, M., Yamashita, T., Arai, K., Terashima, T., Iida, N., Fushimi, K., Yamashita, T., Sakai, Y., Honda, M., Harada, K., Kaneko, S. 2020; 55 (7): 701-711

  Abstract

  The interaction between T-cells/fatty acids involved in non-alcoholic fatty liver disease (NAFLD) and liver fibrosis progression is poorly understood. In this study, we conducted a comprehensive analysis of T-cell profiles of NAFLD patients to better understand their relationship with fatty acids and relevance to liver fibrosis.We analyzed the differences in T-cell profiles of peripheral blood mononuclear cells (PBMCs) between 40 NAFLD patients and 5 healthy volunteers (HVs), and their relationship with liver fibrosis stage or progression. Moreover, we analyzed the relationship between T-cell profiles and fatty acid compositions in vivo, and changes in T-cell profiles after treatment with fatty acids in vitro.T-cell profiles of NAFLD patients were different from those of HVs. The CD25+CD45+CD4+ T-cell frequency was increased in NAFLD patients with high liver fibrosis stage and progression, and this indicated immune activation. Despite such a state of immune activation, the PD1+CD4+ T-cell frequency was decreased in the same patients group. The PD1+CD4+ T-cell frequency had a significantly negative correlation with the serum fatty acid composition ratio C16:1n7/C16:0. Moreover, the PD1+CD4+ T-cell frequency was significantly decreased by in vitro treatment with fatty acids. In addition, its rate of frequency change was significantly different between C16:0 and C16:1n7 and decreased by artificially increasing the C16:1n7/C16:0 ratio.The analysis of PBMCs in NAFLD patients showed that T-cell profiles were different from those of HVs. And, it suggested that fatty acids modified T-cell profiles and were involved in liver fibrosis in NAFLD patients.

  View details for DOI 10.1007/s00535-020-01679-7

  View details for Web of Science ID 000517691000002

  View details for PubMedID 32124081

• Implication of the cooking oil-peroxidation product "hydroxynonenal" for Alzheimer's disease. Frontiers in aging neuroscience Yamashima, T., Seike, T., Mochly-Rosen, D., Chen, C. H., Kikuchi, M., Mizukoshi, E. 2023; 15: 1211141

  Abstract

  Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme that reduces cell injuries via detoxification of lipid-peroxidation product, 4-hydroxy-2-nonenal (hydroxynonenal). It is generated exogenously via deep-frying of linoleic acid-rich cooking oils and/or endogenously via oxidation of fatty acids involved in biomembranes. Although its toxicity for human health is widely accepted, the underlying mechanism long remained unknown. In 1998, Yamashima et al. have formulated the "calpain-cathepsin hypothesis" as a molecular mechanism of ischemic neuronal death. Subsequently, they found that calpain cleaves Hsp70.1 which became vulnerable after the hydroxynonenal-induced carbonylation at the key site Arg469. Since it is the pivotal aberration that induces lysosomal membrane rupture, they suggested that neuronal death in Alzheimer's disease similarly occurs by chronic ischemia via the calpain-cathepsin cascade triggered by hydroxynonenal. For nearly three decades, amyloid β (Aβ) peptide was thought to be a root substance of Alzheimer's disease. However, because of both the insignificant correlations between Aβ depositions and occurrence of neuronal death or dementia, and the negative results of anti-Aβ medicines tested so far in the patients with Alzheimer's disease, the strength of the "amyloid cascade hypothesis" has been weakened. Recent works have suggested that hydroxynonenal is a mediator of programmed cell death not only in the brain, but also in the liver, pancreas, heart, etc. Increment of hydroxynonenal was considered an early event in the development of Alzheimer's disease. This review aims at suggesting ways out of the tunnel, focusing on the implication of hydroxynonenal in this disease. Herein, the mechanism of Alzheimer neuronal death is discussed by focusing on Hsp70.1 with a dual function as chaperone protein and lysosomal stabilizer. We suggest that Aβ is not a culprit of Alzheimer's disease, but merely a byproduct of autophagy/lysosomal failure resulting from hydroxynonenal-induced Hsp70.1 disorder. Enhancing ALDH2 activity to detoxify hydroxynonenal emerges as a promising strategy for preventing and treating Alzheimer's disease.

  View details for DOI 10.3389/fnagi.2023.1211141

  View details for PubMedID 37693644

  View details for PubMedCentralID PMC10486274

• Vegetable Oil-Peroxidation Product 'Hydroxynonenal' Causes Hepatocyte Injury and Steatosis via Hsp70.1 and BHMT Disorders in the Monkey Liver NUTRIENTS Yamashima, T., Mori, Y., Seike, T., Ahmed, S., Boontem, P., Li, S., Oikawa, S., Kobayashi, H., Yamashita, T., Kikuchi, M., Kaneko, S., Mizukoshi, E. 2023; 15 (8)

  Abstract

  Hsp70.1 has a dual function as a chaperone protein and lysosomal stabilizer. In 2009, we reported that calpain-mediated cleavage of carbonylated Hsp70.1 causes neuronal death by inducing lysosomal rupture in the hippocampal CA1 neurons of monkeys after transient brain ischemia. Recently, we also reported that consecutive injections of the vegetable oil-peroxidation product 'hydroxynonenal' induce hepatocyte death via a similar cascade in monkeys. As Hsp70.1 is also related to fatty acid β-oxidation in the liver, its deficiency causes fat accumulation. The genetic deletion of betaine-homocysteine S-methyltransferase (BHMT) was reported to perturb choline metabolism, inducing a decrease in phosphatidylcholine and resulting in hepatic steatosis. Here, focusing on Hsp70.1 and BHMT disorders, we studied the mechanisms of hepatocyte degeneration and steatosis. Monkey liver tissues with and without hydroxynonenal injections were compared using proteomics, immunoblotting, immunohistochemical, and electron microscopy-based analyses. Western blotting showed that neither Hsp70.1 nor BHMT were upregulated, but an increased cleavage was observed in both. Proteomics showed a marked downregulation of Hsp70.1, albeit a two-fold increase in the carbonylated BHMT. Hsp70.1 carbonylation was negligible, in contrast to the ischemic hippocampus, which was associated with ~10-fold increments. Although histologically, the control liver showed very little lipid deposition, numerous tiny lipid droplets were seen within and around the degenerating/dying hepatocytes in monkeys after the hydroxynonenal injections. Electron microscopy showed permeabilization/rupture of lysosomal membranes, dissolution of the mitochondria and rough ER membranes, and proliferation of abnormal peroxisomes. It is probable that the disruption of the rough ER caused impaired synthesis of the Hsp70.1 and BHMT proteins, while impairment of the mitochondria and peroxisomes contributed to the sustained generation of reactive oxygen species. In addition, hydroxynonenal-induced disorders facilitated degeneration and steatosis in the hepatocytes.

  View details for DOI 10.3390/nu15081904

  View details for Web of Science ID 000977194500001

  View details for PubMedID 37111122

  View details for PubMedCentralID PMC10145254

• An Atypical Complication of Chronic Pancreatitis GASTROENTEROLOGY Fuchizaki, U., Nagai, K., Seike, T. 2023; 164 (4): E1-E3

  View details for DOI 10.1053/j.gastro.2022.09.039

  View details for Web of Science ID 000960053100001

  View details for PubMedID 36195168

• Hsp70.1 carbonylation induces lysosomal cell death for lifestyle-related diseases FRONTIERS IN MOLECULAR BIOSCIENCES Yamashima, T., Seike, T., Oikawa, S., Kobayashi, H., Kido, H., Yanagi, M., Yamamiya, D., Li, S., Boontem, P., Mizukoshi, E. 2023; 9: 1063632

  Abstract

  Alzheimer's disease, type 2 diabetes, and non-alcoholic steatohepatitis (NASH) constitute increasingly prevalent disorders. Individuals with type 2 diabetes are well-known to be susceptible to Alzheimer's disease. Although the pathogenesis of each disorder is multifactorial and the causal relation remains poorly understood, reactive oxygen species (ROS)-induced lipid and protein oxidation conceivably plays a common role. Lipid peroxidation product was recently reported to be a key factor also for non-alcoholic steatohepatitis, because of inducing hepatocyte degeneration/death. Here, we focus on implication of the representative lipid-peroxidation product 'hydroxynonenal' for the cell degeneration/death of brain, pancreas, and liver. Since Hsp70.1 has dual roles as a chaperone and lysosomal membrane stabilizer, hydroxynonenal-mediated oxidative injury (carbonylation) of Hsp70.1 was highlighted. After intake of high-fat diets, oxidation of free fatty acids in mitochondria generates ROS which enhance oxidation of ω-6 polyunsaturated fatty acids (PUFA) involved within biomembranes and generate hydroxynonenal. In addition, hydroxynonenal is generated during cooking deep-fried foods with vegetable oils especially containing linoleic acids. These intrinsic and exogenous hydroxynonenal synergically causes an increase in its serum and organ levels to induce Hsp70.1 oxidation. As it is amphiphilic; being water-soluble but displays strong lipophilic characteristics, hydroxynonenal can diffuse within the cells and react with targets like senile and/or atheromatous plaques outside the cells. Hydroxynonenal can deepen and expand lysosomal injuries by facilitating 'calpain-mediated cleavage of the carbonylated Hsp70.1'. Despite the unique anatomical, physiological, and biochemical characteristics of each organ for its specific disease, there should be a common cascade of the cell degeneration/death which is caused by hydroxynonenal. This review aims to implicate hydroxynonenal-mediated Hsp70.1 carbonylation for lysosomal membrane permeabilization/rupture and the resultant cathepsin leakage for inducing cell degeneration/death. Given the tremendous number of worldwide people suffering various lifestyle-related diseases, it is valuable to consider how ω-6 PUFA-rich vegetable oils is implicated for the organ disorder.

  View details for DOI 10.3389/fmolb.2022.1063632

  View details for Web of Science ID 000939622500001

  View details for PubMedID 36819480

  View details for PubMedCentralID PMC9936620

• Unusual Large Nodules in the Colon GASTROENTEROLOGY Fuchizaki, U., Nagai, K., Seike, T. 2023; 164 (1): E10-E11

  View details for DOI 10.1053/j.gastro.2022.08.021

  View details for Web of Science ID 000905721500001

  View details for PubMedID 35964692

• CYTOTOXIC MECHANISM OF HYDROXYNONENAL VIA CALPAIN ACTIVATION IN THE PATHOGENESIS OF NON-ALCOHOLIC STEATOHEPATITIS. Seike, T., Boontem, P., Yanagi, M., Li, S., Kido, H., Daisuke, Y., Yamashima, T., Mizukoshi, E. WILEY. 2022: S823-S824

  View details for Web of Science ID 000870796602296

• Menstrual toxic shock syndrome CANADIAN MEDICAL ASSOCIATION JOURNAL Seike, T., Kanaya, T., Oishi, N. 2022; 194 (26): E936-E937

  View details for DOI 10.1503/cmaj.211284-f

  View details for Web of Science ID 000861986000010

• Menstrual toxic shock syndrome CANADIAN MEDICAL ASSOCIATION JOURNAL Seike, T., Kanaya, T., Oishi, N. 2022; 194 (15): E555

  View details for DOI 10.1503/cmaj.211284

  View details for Web of Science ID 000821055900004

  View details for PubMedID 35440505

  View details for PubMedCentralID PMC9035298

• A Rare Case of Ileocecal Intussusception in an Adult GASTROENTEROLOGY Fuchizaki, U., Seike, T. 2022; 162 (3): E4-E5

  View details for DOI 10.1053/j.gastro.2021.07.014

  View details for Web of Science ID 000833429300002

  View details for PubMedID 34280385

• Gastric Hyperplastic Polyp with Helicobacter suis-infected Gastritis INTERNAL MEDICINE Seike, T., Murayama, S. Y., Nakamura, M., Kobayashi, M. 2022; 61 (16): 2539-2541

  View details for DOI 10.2169/internalmedicine.7779-21

  View details for Web of Science ID 000843964800001

  View details for PubMedID 35110474

  View details for PubMedCentralID PMC9449624

• ELUCIDATION OF THE EFFECT OF HYDROXYNONENAL ON THE PATHOGENESIS OF NASH Yanagi, M., Seike, T., Kido, H., Daisuke, Y., Mizukoshi, E., Kaneko, S. WILEY. 2021: 1063A

  View details for Web of Science ID 000707188005136

• HYDROXYNONENAL CAUSES HEPATOCYTE DEATH BY LYSOSOMAL DISINTEGRITY IN NAFLD. Seike, T., Yanagi, M., Kido, H., Daisuke, Y., Mizukoshi, E., Kaneko, S. WILEY. 2021: 1071A

  View details for Web of Science ID 000707188005151

• Small bowel obstruction caused by intrauterine device infection CLINICAL JOURNAL OF GASTROENTEROLOGY Seike, T., Kanaya, T., Suda, T., Oishi, N. 2021; 14 (5): 1419-1425

  Abstract

  A 39-year-old previously healthy woman was referred to our emergency department by a primary care doctor on suspected to be acute enteritis, complaining of fever, anorexia, lower abdominal pain, and frequent diarrhea. The day after admission, although frequent diarrhea stopped, the abdominal distension worsened. An abdominal radiograph revealed several dilated loops of the small bowel, suggested that small bowel obstruction (SBO) had developed. White blood cell count and c-reactive protein were markedly increased, and abdominal contrast-enhanced computed tomography scan showed localized severely edematous bowel mucosa, increased adipose tissue concentration in the pelvis, and a beaded low absorption area in the uterus. Gynecological examination revealed the presence of a pus-filled plastic intrauterine device (IUD) in the uterus. The patient confided that she had sex with her husband 2 days before the onset of symptoms. A diagnosis of SBO due to pelvic peritonitis caused by IUD infection during sexual activity was made. The SBO was cleared in 12 days with fasting, peripheral parenteral nutrition, antibiotic treatment, and insertion of an ileus tube. This case reminds us that it needs to consider disorders associated with the uterine appendages, in women of reproductive age with lower abdominal pain.

  View details for DOI 10.1007/s12328-021-01476-6

  View details for Web of Science ID 000673027000001

  View details for PubMedID 34255288

  View details for PubMedCentralID 3712202

• Conservative treatment of hepatic portal venous gas resulting from non-occlusive mesenteric ischemia: a case report CLINICAL JOURNAL OF GASTROENTEROLOGY Seike, T., Suda, T., Oishi, N. 2021; 14 (5): 1404-1410

  Abstract

  A 73-year-old man with severe intellectual disability, malnutrition, and hypoalbuminemia presented to our hospital after experiencing vomiting following dinner. Electrocardiography revealed a sinus rhythm. Plain abdominal radiography showed branching radiolucency in the liver. Abdominal computed tomography (CT) revealed branching gaseous foci of low density in the portal vein and its tributaries, suggesting the presence of hepatic portal venous gas (HPVG). Abdominal contrast-enhanced CT showed a segmental lack of contrast enhancement in the intestinal wall despite the absence of vascular occlusion in the main trunk and branches of the mesenteric artery. The patient was diagnosed with non-occlusive mesenteric ischemia (NOMI) accompanied by HPVG. Peripheral parenteral nutrition, antibiotic treatment, and human serum albumin were administered. The HPVG disappeared approximately 20 h after hospitalization. Intravascular dehydration associated with hypoalbuminemia was considered to be the cause of NOMI; the latter improved through the early correction of dehydration and hypoalbuminemia. The presence of HPVG is usually considered a diagnostic clue in patients with abdominal catastrophe and is associated with high mortality. However, the current case demonstrates the pitfalls of assessing the severity of the underlying condition based solely on the presence of HPVG.

  View details for DOI 10.1007/s12328-021-01468-6

  View details for Web of Science ID 000668231400002

  View details for PubMedID 34173209

  View details for PubMedCentralID 3605538

• T-CELL PROFILES MODIFIED BY FATTY ACIDS WERE ASSOCIATED WITH LIVER FIBROSIS IN NON-ALCOHOLIC FATTY LIVER DISEASE PATIENTS. Seike, T., Mizukoshi, E., Kaneko, S. WILEY. 2020: 1056-1057

  View details for Web of Science ID 000574027004187

• Diagnosis of biliary varices using digital cholangioscopy ENDOSCOPY INTERNATIONAL OPEN Suda, T., Omizo, T., Yoshida, R., Seike, T., Oishi, N., Matsushita, E. 2020; 08 (10): E1437-E1438

  View details for DOI 10.1055/a-1236-3421

  View details for Web of Science ID 000583033800033

  View details for PubMedID 33015349

  View details for PubMedCentralID PMC7508654

• A Case of Anaphylaxis with Mild Abdominal Pain Due to Gastroallergic Anisakiasis AMERICAN JOURNAL OF MEDICINE Seike, T., Kobayashi, M., Suda, T., Oishi, N. 2020; 133 (10): E601-E602

  View details for DOI 10.1016/j.amjmed.2020.02.054

  View details for Web of Science ID 000577506000018

  View details for PubMedID 32289306

• The S-O clip closure method: a novel method for closing large mucosal defects ENDOSCOPY INTERNATIONAL OPEN Suda, T., Omizo, T., Seike, T., Oishi, N. 2020; 08 (09): E1163-E1164

  View details for DOI 10.1055/a-1191-2863

  View details for Web of Science ID 000564256200011

  View details for PubMedID 32904808

  View details for PubMedCentralID PMC7458731

• Successful closure of a colon perforation via the over-the-scope-clip system after accidental ingestion of a fish bone ENDOSCOPY Suda, T., Soga, S., Oishi, N., Seike, T., Hirose, K. 2020; 52 (4): E126-E127

  View details for DOI 10.1055/a-1024-3373

  View details for Web of Science ID 000529224000011

  View details for PubMedID 31652474

• The Serum Mac-2-binding Protein Glycosylation Isomer Dynamics in Acute Liver Injury INTERNAL MEDICINE Seike, T., Komura, T., Shimizu, Y., Omura, H., Kumai, T., Kagaya, T., Ohta, H., Kawashima, A., Harada, K., Kaneko, S., Unoura, M. 2020; 59 (13): 1581-1588

  Abstract

  Objective We aimed to examine the dynamics of serum Wisteria floribunda agglutinin-positive human Mac-2-binding protein glycosylation isomer (M2BPGi) in patients with acute liver injury. Methods Serum M2BPGi levels at the time of the diagnosis (n=77) and normalization of the serum alanine aminotransferase (ALT) level (n=26) were examined retrospectively. The difference in the serum M2BPGi level according to the etiology, and the correlations with other laboratory parameters were evaluated. Results The serum M2BPGi level at the time of the diagnosis was increased in 59 of 77 patients [2.3 cutoff index (COI); range, 0.31-11.1 COI] and was significantly decreased at the time of serum ALT normalization (0.68 COI; range, 0.15-1.87 COI; p<0.0001). The serum M2BPGi level was positively correlated with the duration for which serum ALT normalization was achieved (n=46, Spearman rho=0.53, p<0.0001). A multivariate analysis identified total bilirubin (T-bil), albumin, ALT, alkaline phosphatase, and etiology (e.g., drug-induced liver injury or etiology unknown) as independent factors for increased serum M2BPGi. In patients with infectious mononucleosis, the serum M2BPGi level was higher relative to the degree of increase of serum ALT or T-bil levels in comparison to other etiologies. Conclusion The serum M2BPGi level in patients with acute liver injury reflects the magnitude and duration of liver injury. However, it should be noted that the degree of increase of serum M2BPGi in patients with acute liver injury may differ according to the etiology.

  View details for DOI 10.2169/internalmedicine.3867-19

  View details for Web of Science ID 000551130800001

  View details for PubMedID 32269188

  View details for PubMedCentralID PMC7402970

• A case of small bowel adenocarcinoma that caused intestinal obstruction after administration of patency capsule CLINICAL JOURNAL OF GASTROENTEROLOGY Seike, T., Yamato, M., Suda, T., Soga, S., Kobayashi, M., Hirose, K., Oishi, N. 2020; 13 (4): 522-526

  Abstract

  An 80-year-old man was admitted to our hospital with iron deficiency anemia and exertional chest pain. Coronary artery angiography showed 90% stenosis in the middle left anterior descending branch; abdominal computed tomography (CT) showed enlarged mesenteric lymph nodes. Although his past medical history and results of imaging studies did not suggest intestinal stenosis, assessment of intestinal patency with the PillCam® patency capsule (tag-less PC) was performed. Thirty-three hours after administration, excretion of tag-less PC was not confirmed; an abdominal contrast-enhanced CT showed arrest of tag-less PC in the small bowel and thickening of the bowel wall, suggesting a small bowel tumor. Four days after administration of tag-less PC, he developed abdominal pain and vomiting. Intestinal obstruction was diagnosed by abdominal radiograph. A diagnosis of small bowel tumor with intestinal obstruction was made, and surgical resection was performed. The tumor was histologically an adenocarcinoma. It is necessary to carefully evaluate gastrointestinal patency before small intestine endoscopy especially in elderly people with reduced cardiopulmonary function and many underlying diseases.

  View details for DOI 10.1007/s12328-019-01084-5

  View details for Web of Science ID 000549891400001

  View details for PubMedID 31893340

• Serum C16:1n7/C16:0 ratio as a diagnostic marker for non-alcoholic steatohepatitis JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY Yamada, K., Mizukoshi, E., Seike, T., Horii, R., Terashima, T., Iida, N., Kitahara, M., Sunagozaka, H., Arai, K., Yamashita, T., Honda, M., Takamura, T., Harada, K., Kaneko, S. 2019; 34 (10): 1829-1835

  Abstract

  Accurate diagnosis of non-alcoholic steatohepatitis (NASH) from non-alcoholic fatty liver disease (NAFLD) is clinically important. Therefore, there is a need for easier ways of diagnosing NASH. In this study, we investigated the serum fatty acid composition and evaluated the possibility of using the serum fatty acid composition as a diagnostic marker of NASH.The subjects were 78 NAFLD patients (non-alcoholic fatty liver [NAFL]: 30, NASH: 48) and 24 healthy individuals. Fatty acids extracted from the liver tissue and serum were identified and quantified by gas chromatography. In addition, we evaluated the relationship between serum and liver tissue fatty acid composition, patient background, and liver histology. The diagnostic performance of NASH was evaluated by calculating the area under the receiver operating characteristic (AUROC).The results of the fatty acid analysis showed the C16:1n7/C16:0 ratio to have the strongest correlation between serum and liver tissue (r = 0.865, P < 0.0001). The serum C16:1n7/C16:0 ratio in the NASH group was higher compared with that in the NAFL group (P = 0.0007). Evaluation of the association of the serum C16:1n7/C16:0 ratio with liver histology revealed significant correlation with lobular inflammation score, ballooning score, and fibrosis score. The AUROC for predicting NASH in all NAFLD patients was 0.7097. The AUROC was nearly equivalent even when the study subjects were restricted to patients with a fibrosis score ≤ 2 only (AUROC 0.6917).Measuring the serum C16:1n7/C16:0 ratio may be an effective non-invasive method for diagnosing NASH, particularly in its early stages.

  View details for DOI 10.1111/jgh.14654

  View details for Web of Science ID 000496399200027

  View details for PubMedID 30864239

• EFFECTS OF FATTY ACID METABOLISM ON HOST IMMUNE RESPONSE IN NON-ALCOHOLIC FATTY LIVER DISEASE PATIENTS Seike, T., Mizukoshi, E., Yamada, K., Kitahara, M., Yamashita, T., Arai, K., Terashima, T., Iida, N., Fushimi, K., Yamashita, T., Sakai, Y., Honda, M., Kaneko, S. WILEY. 2019: 1322A

  View details for Web of Science ID 000488653504517

• A case of chronic pancreatitis exacerbation associated with pancreatic arteriovenous malformation: a case report and literature review CLINICAL JOURNAL OF GASTROENTEROLOGY Seike, T., Komura, T., Shimizu, Y., Omura, H., Kumai, T., Kagaya, T., Ohta, H., Kawashima, A., Harada, K., Kaneko, S., Unoura, M. 2019; 12 (2): 135-141

  Abstract

  A 60-year-old man with an unruptured cerebral aneurysm and family history of moyamoya disease was admitted to our hospital with epigastric pain since the previous day. Serum levels of pancreatic enzyme were elevated and abdominal contrast-enhanced computed tomography showed localized enlargement of the pancreatic tail in the arterial phase and revealed numerous areas of fine mesh-like vascular hyperplasia consistent with an enlarged pancreatic tail. We diagnosed pancreatic arteriovenous malformation (P-AVM) with acute pancreatitis. Furthermore, in the pancreatic body, endoscopic ultrasonography showed lobularity (honeycombing type) and hyperechoic foci (non-shadowing), which suggests chronic pancreatitis. Acute management was performed with conservative treatment including administration of replacement fluids and proteolytic enzyme inhibitor. Distal pancreatectomy for P-AVM was performed because P-AVM is associated with acute pancreatitis recurrence, development of portal hypertension, progression of chronic pancreatitis, and refractory duodenal bleeding. Histological findings on the resected specimens revealed the anastomosis of abnormal arteries and veins, which suggested P-AVM. In addition, inflammation accompanied by fat necrosis due to ischemic infarction in the pancreatic tail, which suggested acute pancreatitis, and mild fibrosis in the pancreatic body, which suggested chronic pancreatitis, were shown. Although P-AVM is associated with various complications, symptomatic P-AVM should be considered a chronic and progressive disease.

  View details for DOI 10.1007/s12328-018-0901-1

  View details for Web of Science ID 000462908200007

  View details for PubMedID 30182162

• Characteristics of Immune Response to Tumor-Associated Antigens and Immune Cell Profile in Patients With Hepatocellular Carcinoma HEPATOLOGY Inada, Y., Mizukoshi, E., Seike, T., Tamai, T., Iida, N., Kitahara, M., Yamashita, T., Arai, K., Terashima, T., Fushimi, K., Yamashita, T., Honda, M., Kaneko, S. 2019; 69 (2): 653-665

  Abstract

  Host antitumor immune responses may be different between hepatocellular carcinoma (HCC) caused by metabolic disorders and HCC associated with hepatitis virus infection. In this study, we examined the immune response of tumor-associated antigen (TAA)-specific T cells and immune cell profile in patients with HCC separated by cause. Thirty-two patients with hepatitis B virus (HBV)-related HCC, 42 patients with hepatitis C virus-related HCC, and 18 patients with nonalcoholic steatohepatitis (NASH)-related HCC were analyzed. The frequencies of TAA-specific T cells, the expression levels of surface markers on each immune cell, and the expression of each TAA in HCC tissue were measured. The immune response to TAA and immune cell profile were markedly different among the three groups. The immune response to TAA in the NASH-related HCC group was weaker than the responses in the other two groups. In patients with NASH-related HCC, the frequencies of effector regulatory T cells (eTregs) and cluster of differentiation 8-positive (CD8+ ) T cells strongly expressing cytotoxic T-lymphocyte antigen (CTLA)-4 were high. The frequency of CD8+ T cells strongly expressing programmed cell death 1 was the highest in patients with HBV-related HCC. Among these immune cell profiles, the frequencies of C-X-C motif chemokine receptor 3+ eTregs and CTLA-4+ CD8+ T cells were inversely correlated with the strength of the TAA-specific T-cell immune response, and the restoration of TAA-specific T-cell responses by anti-CTLA-4 antibody was observed. Conclusion: The immune response to TAA were markedly different among the three groups, and a correlation with the immune cell profile was observed, suggesting that development of immunotherapy based on the etiology of HCC may lead to more effective treatment outcomes.

  View details for DOI 10.1002/hep.30212

  View details for Web of Science ID 000457447700016

  View details for PubMedID 30102778

• A case of an elderly female with diffuse hepatic hemangiomatosis complicated with multiple organic dysfunction and Kasabach-Merritt syndrome CLINICAL JOURNAL OF GASTROENTEROLOGY Shimizu, Y., Komura, T., Seike, T., Omura, H., Kumai, T., Kagaya, T., Ohta, H., Kawashima, A., Harada, K., Kaneko, S., Unoura, M. 2018; 11 (5): 411-416

  Abstract

  Since diffuse hepatic hemangiomatosis (DHH) is an extremely rare disease especially in adults, the etiology and natural course of adult-onset DHH has not been well understood. We report a case of DHH complicated with multiple organic dysfunction and Kasabach-Merritt syndrome (KMS) in an 83-year-old female. She presented with mild abdominal distension and laboratory findings revealed thrombocytopenia and abnormal coagulation, indicating disseminated intravascular coagulation (DIC). Enhanced computed tomography revealed diffuse, hypodense hepatic nodules with delayed enhancement involving the whole liver, and multiple hypodense splenic legions. To obtain a definitive diagnosis, laparoscopic-guided biopsy was performed. Histological findings revealed irregularly dilated non-anastomotic vascular spaces, which were lined with flat endothelial cells without cellular atypia. We diagnosed this as DHH complicated with splenic lesions and KMS. Although the patient was treated with symptomatic treatment, such as anti-coagulation therapy, hemangiomatous lesions, especially in the spleen, progressed rapidly, leading to worsening of DIC. Finally, the patient died of multiple organ failure at 12 months after diagnosis. A postmortem examination demonstrated diffuse hemangiomatosis of not only the liver and spleen, but also the adrenal glands and bone marrow. Despite no malignant histologically, DHH can be fatal if it progresses rapidly within a short period of time.

  View details for DOI 10.1007/s12328-018-0871-3

  View details for Web of Science ID 000445624500013

  View details for PubMedID 29845554

• Immune Response to Tumor-Associated Antigens and Immune Cell Profiles in Nash-Related Hepatocellular Carcinoma Seike, T., Mizukoshi, E., Inada, Y., Tamai, T., Iida, N., Kitahara, M., Yamashita, T., Arai, K., Terashima, T., Fushimi, K., Yamashita, T., Honda, M., Kaneko, S. WILEY. 2018: 1256A

  View details for Web of Science ID 000446020503441

• Light alcohol consumption has the potential to suppress hepatocellular injury and liver fibrosis in non-alcoholic fatty liver disease PLOS ONE Yamada, K., Mizukoshi, E., Seike, T., Horii, R., Kitahara, M., Sunagozaka, H., Arai, K., Yamashita, T., Honda, M., Kaneko, S. 2018; 13 (1): e0191026

  Abstract

  The modest consumption of alcohol has been reported to decrease the incidence of fatty liver or prevalence of steatohepatitis. In this study, we investigated the effect of light alcohol consumption on liver function and gene expression in patients with non-alcoholic fatty liver disease (NAFLD).The study group was formed of 178 patients diagnosed with non-alcoholic fatty liver disease, subclassified into two groups for analysis based on the daily alcohol consumption: non-alcohol group and light alcohol consumer group (≤20 g of ethanol/day). Clinical characteristics, liver histological features, gene expression, comprehensively analyzed using microarrays (BRB-Array tools), and molecular network were evaluated and compared between the two groups.No significant differences in steatosis or inflammation score were noted among the groups. However, the ballooning and fibrosis scores were significantly lower in the light alcohol consumer group than in the non-alcohol group. Gene expression analysis revealed a marked inhibition of the pathways involved in the immune response in the light alcohol group compared to that in the non-alcohol group.Light alcohol consumption might suppress activity of non-alcoholic steatohepatitis by reducing gene expression levels involved in the immune response. This inhibition in gene expression was associated with a lowering of liver fibrosis and hepatocellular injury.

  View details for DOI 10.1371/journal.pone.0191026

  View details for Web of Science ID 000422653800041

  View details for PubMedID 29342182

  View details for PubMedCentralID PMC5771612

• A Young Man with Non-alcoholic Steatohepatitis and Serum Anti-mitochondrial Antibody Positivity INTERNAL MEDICINE Seike, T., Komura, T., Shimizu, Y., Omura, H., Kumai, T., Kagaya, T., Ohta, H., Kawashima, A., Harada, K., Kaneko, S., Unoura, M. 2018; 57 (21): 3093-3097

  Abstract

  A 37-year-old obese man who was a social drinker was admitted to our hospital to undergo a detailed examination for liver injury with anti-mitochondrial antibody positivity. Abdominal ultrasonography revealed moderate fatty liver. A histological analysis showed steatosis of approximately 30% of the hepatocytes, focal necrosis, a few ballooning hepatocytes and lobular inflammation suggestive of steatohepatitis, epithelioid granuloma and irregularity of the sequence of the bile duct epithelium accompanied by lymphocyte infiltration suggestive of chronic cholangitis. He was diagnosed with non-alcoholic steatohepatitis complicated with primary biliary cholangitis. His liver injury was improved by weight loss and high-dose ursodeoxycholic acid treatment.

  View details for DOI 10.2169/internalmedicine.0405-17

  View details for Web of Science ID 000449328100006

  View details for PubMedID 29877264

  View details for PubMedCentralID PMC6262692

• The Efficacy of Corticosteroid Therapy in a Patient with Non-alcoholic Steatohepatitis Overlapping Autoimmune Hepatitis INTERNAL MEDICINE Komura, T., Ohta, H., Seike, T., Shimizu, Y., Nakai, R., Omura, H., Kagaya, T., Kasashima, S., Kawashima, A., Oba, S., Harada, K., Kaneko, S., Unoura, M. 2018; 57 (6): 807-812

  Abstract

  The overlap of multiple liver diseases can cause the disease activity and severity to worsen rapidly in some cases. We rarely see patients with non-alcoholic steatohepatitis (NASH) with overlapping autoimmune hepatitis (AIH). A 64-year-old woman who had been prescribed oral drugs to treat diabetes and hypertension (metformin 500 mg/day and voglibose 0.9 mg/day, and termisartan 40 mg/day and amlodipine 5 mg/day, respectively) was diagnosed with NASH with histological confirmation. At 68 years of age, her liver injury worsened with an IgG of 2,871 mg/dL and a high serum anti-nuclear antibody (ANA) level of 2,560. We repeated the liver biopsy, which revealed NASH and mild interface hepatitis with some lobular focal necrosis consisting of overlapping AIH. Therefore, she was treated with 30 mg of prednisolone daily. The treatment led to an improvement in her IgG levels and ANA in the serum and an improvement in the histology results.

  View details for DOI 10.2169/internalmedicine.8887-17

  View details for Web of Science ID 000427750700008

  View details for PubMedID 29151501

  View details for PubMedCentralID PMC5891518

• [A case of gastric follicular lymphoma resected and diagnosed with laparoscopy and endoscopy cooperative surgery]. Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology Seike, T., Inamura, K., Okuno, N., Asaumi, Y., Takata, Y., Okamura, T., Matano, S., Terahata, S., Sakatoku, K., Kawai, H. 2017; 114 (11): 1996-2004

  Abstract

  A woman in her 70s was diagnosed with a protruding mucosa-associated lymphoid tissue (MALT) lymphoma during a secondary health examination. After eradication of Helicobacter pylori, a biopsy revealed gastric follicular lymphoma (FL) and the lesion was still protruding one year later. 18F-fluorodeoxyglucose positron emission tomography showed focal nodular hypermetabolic activity, suggesting that FL may have transformed into a diffuse large B-cell lymphoma. Upper gastrointestinal endoscopy, colonoscopy, and capsule endoscopy showed no other lesions in the gastrointestinal tract, and bone marrow biopsy showed no permeation into the marrow. Therefore, this lesion, which appeared as a submucosal tumor, was limited to the stomach. Laparoscopy and endoscopy cooperative surgery was performed, because it allows for correct pathological diagnosis while removing only a minimal portion of the stomach wall. Histological findings showed follicular structures consisting of abnormal lymphoid cells. Immunohistochemical analysis revealed that neoplastic cells were positive for CD20, CD79a, Bcl-2, CD10, and c-MYC, but negative for CD3, CD5, and cyclin D1. Finally, we diagnosed this lesion as a primary gastric FL.

  View details for DOI 10.11405/nisshoshi.114.1996

  View details for PubMedID 29109348

• The utility of the serum C16:1n7/C16:0 ratio as a diagnostic marker of non-alcoholic steatohepatitis Yamada, K., Mizukoshi, E., Seike, T., Terashima, T., Kitahara, M., Iida, N., Sunagozaka, H., Arai, K., Yamashita, T., Honda, M., Kaneko, S. WILEY. 2017: 1091A

  View details for Web of Science ID 000412089802421

• The CD25 expression on CD4+FoxP3-T cells in non-alcoholic fatty liver disease Seike, T., Mizukoshi, E., Tamai, T., Terashima, T., Iida, N., Yamashita, T., Arai, K., Yamada, K., Kaneko, S. WILEY. 2017: 1068A-1069A

  View details for Web of Science ID 000412089802376

• [A case of cytomegalovirus infection with splenic infarction and an esophageal ulcer in an immunocompetent adult]. Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology Shimizu, Y., Komura, T., Seike, T., Nakai, R., Omura, H., Kagaya, T., Ohta, H., Kasashima, S., Kawashima, A., Unoura, M. 2017; 114 (7): 1269-1276

  Abstract

  Recently, morbidities due to primary cytomegalovirus (CMV) infection have increased in young Japanese adults because of decreased anti-CMV antibodies in them. CMV infections are typically resolved naturally in immunocompetent individuals, and complications rarely occur. Here we present the case of an immunocompetent adult with CMV infection complicated by splenic infarctions and an esophageal ulcer.A 37-year-old male complaining of a prolonged fever and liver injury was admitted to hospital for a closed examination. The patient had general malaise and mild appetite loss but no abdominal pain. Symptoms of infectious mononucleosis, including liver injury, appearance of atypical lymphocytes in the blood, and hepatosplenomegaly, were observed. A primary CMV infection was confirmed by CMV-IgM positive and CMV-IgG negative serological tests. Enhanced abdominal computed tomography confirmed hepatitis and splenic infarction, and an upper gastrointestinal endoscopy revealed an esophageal ulcer. The patient exhibited no predisposing risk factors for thrombosis, and he was diagnosed with splenic infarctions associated with CMV infection. Because the patient was immunocompetent, he underwent symptomatic therapy without antiviral or anticoagulant therapies. The treatment improved his overall condition. Including the present case, only 11 cases of CMV infections with splenic infarction in immunocompetent individuals have been reported. Contrary to what is observed in immunocompromised hosts, upper gastrointestinal lesions with CMV infection are rare in immunocompetent individuals. The esophageal lesion observed in our patient was a typical punched-out ulcer. The immunohistochemical staining of the tissue biopsies revealed that the ulcer was associated with CMV.Although splenic infarctions and esophageal ulcers are rare, they should be considered as potential complications accompanying CMV infection in immunocompetent individuals. The administration of symptomatic therapy should be considered even when the patient is immunocompetent.

  View details for DOI 10.11405/nisshoshi.114.1269

  View details for PubMedID 28679983

• [A rapidly growing, large, mature retroperitoneal teratoma in an adult male patient]. Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology Seike, T., Kagaya, T., Komura, T., Nakai, R., Shimizu, Y., Omura, H., Ohta, H., Ohyama, S., Kawashima, A., Unoura, M. 2017; 114 (6): 1008-1014

  Abstract

  A 40-year-old man complaining of abdominal distention was referred to our hospital. Computed tomography of the abdomen demonstrated a very large abdominal mass with fat and calcification. The size of the mass rapidly increased from 30cm to 40cm over two weeks. The tumor was removed and diagnosed by pathological examination to be a retroperitoneal mature cystic teratoma that contained a 40-cm long, mature intestinal tract-like cyst, together with bone marrow and fat. The rapid growth of the tumor may have been caused by an increased secretion in the cyst.

  View details for DOI 10.11405/nisshoshi.114.1008

  View details for PubMedID 28579584

• Lidocaine spray alone is similar to spray plus viscous solution for pharyngeal observation during transoral endoscopy: a clinical randomized trial ENDOSCOPY INTERNATIONAL OPEN Hayashi, T., Asahina, Y., Waseda, Y., Kitamura, K., Kagaya, T., Seike, T., Okada, K., Inada, Y., Takabatake, H., Orita, N., Yanase, Y., Yamashita, T., Ninomiya, I., Yoshimura, K., Kaneko, S. 2017; 5 (1): E47-E53

  Abstract

  Background and study aims It is important to examine the pharynx during upper gastrointestinal endoscopy. Pharyngeal anesthesia using topical lidocaine is generally used as pretreatment. In Japan, lidocaine viscous solution is the anesthetic of choice, but lidocaine spray is applied when the former is considered insufficient. However, the relationship between the extent of pharyngeal anesthesia and accuracy of observation is unclear. We compared the performance of lidocaine spray alone versus lidocaine spray combined with lidocaine viscous solution for pharyngeal observation during transoral endoscopy. Patients and methods In this prospective, double-blinded, randomized clinical trial conducted between January and March 2015, 327 patients were randomly assigned to lidocaine spray alone (spray group, n = 157) or a combination of spray and viscous solution (combination group, n = 170). We compared the number of pharyngeal observable sites (non-inferiority test), pain by visual analogue scale, observation time, and the number of gag reflexes between the two groups. Results The mean number of images of suitable quality taken at the observable pharyngeal sites in the spray group was 8.33 (95 % confidence interval [CI]: 7.94 - 8.72) per patient, and 8.77 (95 % CI: 8.49 - 9.05) per patient in the combination group. The difference in the number of observable pharyngeal sites was - 0.44 (95 % CI: - 0.84 to - 0.03, P = 0.01). There were no differences in pain, observation time, or number of gag reflexes between the 2 groups. Subgroup analysis of the presence of sedation revealed no differences between the two groups for the number of pharyngeal observation sites and the number of gag reflexes. However, the number of gag reflexes was higher in the spray group compared to the combination group in a subgroup analysis that looked at the absence of sedation. Conclusions Lidocaine spray for pharyngeal anesthesia was not inferior to lidocaine spray and viscous solution in terms of pharyngeal observation. It was considered that lidocaine viscous solution was unnecessary for pharyngeal observation. UMIN000016073.

  View details for DOI 10.1055/s-0042-120414

  View details for Web of Science ID 000396368800008

  View details for PubMedID 28191496

  View details for PubMedCentralID PMC5291156

• Immunological characteristics of the tumor-associated antigens in patients with cholangiocarcinoma Kida, A., Mizukoshi, E., Seike, T., Yonejima, A., Inada, Y., Kaji, K., Yamada, K., Nakagawa, H., Terashima, T., Kitahara, M., lida, N., Kaneko, S., Kaneko, C. WILEY. 2016: 628A-629A

  View details for Web of Science ID 000385493803058

• Lidocaine Spray Alone Is Similar to Lidocaine Spray Plus Viscous Solution for Pharyngeal Observation During Transoral Endoscopy: A Randomized Prospective Study Hayashi, T., Asahina, Y., Waseda, Y., Kitamura, K., Kagaya, T., Seike, T., Inada, Y., Takabatake, H., Orita, N., Yanase, Y., Yamashita, T., Ninomiya, I., Yoshimura, K., Kaneko, S. MOSBY-ELSEVIER. 2016: AB225

  View details for DOI 10.1016/j.gie.2016.03.295

  View details for Web of Science ID 000381906900276

• Imaging findings of gastric calcifying fibrous tumour BJR CASE REPORTS Miyashita, S., Ryu, Y., Takata, H., Asaumi, Y., Sakatoku, M., Seike, T., Okamura, T., Inamura, K., Kawai, H., Okuno, N., Terahata, S. 2016; 2 (4): 20160064

  Abstract

  Calcifying fibrous tumours (CFTs) are rare benign lesions that usually affect the soft tissues, the mesentery and the peritoneum. Gastric CFT is particularly rare. Here, we report a CFT found incidentally in a 31-year-old male. The mass was well circumscribed and showed partial calcification on the CT scan, with dark signal intensity seen on T2 weighted MRI. To the best of our knowledge, there is very limited published information concerning imaging findings of CFTs. We discuss the CT scan and MRI findings of this patient, which can be considered typical for gastric CFT, and present a review of the limited literature available.

  View details for DOI 10.1259/bjrcr.20160064

  View details for Web of Science ID 000406883400040

  View details for PubMedID 30460039

  View details for PubMedCentralID PMC6243330